ABSTRACT Critical-sized cranial defects are one of the most clinically relevant situations in civilians as it encountered in congenital anomalies, trauma, stroke, aneurysms, and cancer. Critical-sized bone defects in the cranial region can cause damage leading to noticeable deformity and dysfunction. It is a significant challenge to regenerate cranial bones across gaps exceeding critical size. Application of free vascularized bone graft from distant sites may represent the most reliable procedure, but is inadequate to treat cranial deficits incurred in traumatic brain injuries due to size and shape mismatch. Most synthetic materials often fail to remodel and integrate with host tissue, easily become infected, and lead to multiple revision surgeries. There is an urgent need to develop an absorbable synthetic bone graft that can eliminate the need for a second surgical site to harvest autologous bone and issues associated with the use of allografts. The primary objective is to develop and validate absorbable 3D hybrid nanofiber aerogels that topically deliver various ions and small molecules (e.g. bone morphogenic protein-2 (BMP2) derived peptides) in a controlled and sustained manner for enhancing cellular infiltration, neovascularization, and bone regeneration. We recently showed the fabrication of bioactive glass nanofibers with binary doping of strontium and copper and these fibers demonstrated their bioactivity by promoting osteoblastic and endothelial cell activity and inhibiting the formation of osteoclasts. We further developed a method for generating 3D hybrid nanofiber aerogels made of segmented poly(lactide-co-glycolide) (PLGA 50:50)/collagen nanofibers and strontium and copper doped bioactive glass nanofibers. Working with Dr. Teusink (Co-I), we also demonstrated that such aerogels incorporated with BMP2 peptides significantly enhanced bone regeneration in a rat critical size calvarial defect. Based on these findings, it is hypothesized that local delivery of BMP2 peptides and trace metal ions (Sr2+, Cu2+) from 3D hybrid nanofiber aerogels could greatly promote cellular ingrowth, angiogenesis and bone regeneration. To test the hypothesis and accomplish the primary objective, our strategy is two-fold: i) Establish effective coupling of modified BMP2 peptides with 3D hybrid nanofiber aerogels and examine their cell response in vitro; and ii) Determine the bone regenerative capacity of BMP2 peptide incorporated 3D aerogels using a critical-sized rat calvarial bone defect model. We expect to identify the critical factors of 3D aerogels that contribute to cellular ingrowth, angiogenesis and bone regeneration. Also, we expect successful completion of this proposed study to lay the foundation for developing synthetic bone grafts with a new mechanism of action that could greatly accelerate healing of large cranial bone defects. The 3D aerogels could also be useful in wound healing and regeneration of other tissues. Also, the knowledge gained from completion of the proposed research will contribute significantly to a broad understanding of cell-material interaction and the molecular mechanisms by which ions eluted from bioactive glass nanofibers and BMP2 peptides released from aerogels enhance cranial bone regeneration.